Deoxyribonucleic acid, DNA, consists of two paired complementary strands containing four "bases" in a particular order which specifies the amino acid sequences of various proteins and also controls when and where in the body these proteins are produced. Each human cell contains two copies of this information, each copy consisting of three billion base pairs of DNA divided between 23 chromosomes, encoding about 50,000 genes (genes on the female sex, or "X" chromosome, are present in a single copy in males). This information must be copied faithfully every time a cell divides. While the fidelity of this copying is extremely good, there are occasional errors, and DNA may also be damaged between cell divisions. If such a mutation occurs in germ cell DNA it will be inherited by that individual's offspring. If the mutation alters the function or amount of a protein, it may be evident as an inherited disease. Most often both copies of a gene must be defective (i.e., the defect must be "homozygous") to produce a detectable problem; such diseases are referred to as "autosomal recessive" disorders. When a gene is on the X chromosome, males carrying a single copy of the defective gene may be affected (a "sex-linked recessive" disorder). If "heterozygous" individuals carryiny only one defective gene are affected, the disorder is said to be "dominant".
While several thousand inherited disorders have been described, the defective protein has been identified in only a few hundred; the specific nature of the defect is known in a small fraction of these. Of clinical importance, it has often been impossible to identify heterozygous carriers of an inherited recessive disease, and after an affected child has been born in a family, it has sometimes proven impossible to prenatally diagnose future affected offspring. Cytochromes P-450 are heme-containing enzymes with molecular weights of about 50,000. They all act as terminal oxidases of NADPH-dependent electron transport pathways, but they vary as to substrate specificity and ogan distribution. Several hepatic cytochromes P-450 can be induced to high levels by xenobiotics such as phenobarbital or methylcholanthrene, and it is these enzymes that have been best characterized structurally (1) and on the molecular genetic level (2,3). A number of cytochromes P-450 in the liver, gonads, and adrenal cortex metabolize steroids. The conversion in the adrenal cortex of 17-hydroxyprogesterone to 11-deoxycortisol by 21-hydroxylation was, in fact, the first function assigned to a cytochrome P-450 (P-450) (4). Of the five steps required to synthesize cortisol from cholesterol, four require a P-450 (5): C-22,27 side chain is cleaved by a P-450 to form pregnenolone; the 3.beta.-hydroxyl is dehydrogenated, yielding progesterone, which is successively hydroxylated by three different cytochromes P-450 at the 17.alpha., 21, and 11.beta. positions to yield cortisol. These steps occur in two subcellular locations, the side-chain cleavage and 11.beta.-hydroxylation steps in mitochondria, and the 17.alpha.- and 21-hydroxylations in microsomes.
In humans, genetic defects in each of the steps of cortisol biosynthesis have been described, although only in deficiency of cholesterol side-chain cleavage activity has a defective or deficient P-450 been documented (6). Of these inborn errors of metabolism, 21-hydroxylase deficiency is by far the most common, occurring in about 1/5000 individuals in most populations (7). It is inherited as a monogenic autosomal recessive trait closely linked to the HLA gene complex (8).
The HLA link is described by M. S. Pollack et al. in the Lancet May 26, 1979: